ArticlePloS one2012
A proton leak current through the cardiac sodium channel is linked to mixed arrhythmia and the dilated cardiomyopathy phenotype.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 65 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
65 citing papers in PubMed, 104 citations in OpenAlex.
- Article
- Article
- The differential impacts of equivalent gating-charge mutations in voltage-gated sodium channels.The Journal of general physiology · 2025Article
- Charge Reversal of the Uppermost Arginine in Sliding Helix S4-I Affects Gating of Cardiac Sodium Channel.International journal of molecular sciences · 2025Article
- The many faces of SCN5A pathogenic variants: from channelopathy to cardiomyopathy.Heart failure reviews · 2025Review
- ELUCIDATING THE DIFFERENTIAL IMPACTS OF EQUIVALENT GATING-CHARGE MUTATIONS IN VOLTAGE-GATED SODIUM CHANNELS.bioRxiv : the preprint server for biology · 2024Article
- Genetic background determines the severity of age-dependent cardiac structural abnormalities and arrhythmia susceptibility in Scn5a-1798insD mice.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2024Article
- Pathogenic gating pore current conducted by autism-related mutations in the NaProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Ion currents through the voltage sensor domain of distinct families of proteins.Journal of biological physics · 2023Review
- Maturation of iPSC-derived cardiomyocytes in a heart-on-a-chip device enables modeling of dilated cardiomyopathy caused by R222Q-SCN5A mutation.Biomaterials · 2023Article
- Fifty years of gating currents and channel gating.The Journal of general physiology · 2023Review
- Review
- Optical measurement of gating pore currents in hypokalemic periodic paralysis model cells.Disease models & mechanisms · 2023Article
- Multifocal ectopic purkinje-related premature contractions and related cardiomyopathy.Frontiers in cardiovascular medicine · 2023Review
- Single coronary artery presenting dilated cardiomyopathy and hyperlipidemia with theFrontiers in cardiovascular medicine · 2023Review
- A TRPM7 mutation linked to familial trigeminal neuralgia: Omega current and hyperexcitability of trigeminal ganglion neurons.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Arrhythmias as Presentation of Genetic Cardiomyopathy.Circulation research · 2022Review
- Late Sodium Current of the Heart: Where Do We Stand and Where Are We Going?Pharmaceuticals (Basel, Switzerland) · 2022Review
- 3D models of dilated cardiomyopathy: Shaping the chemical, physical and topographical properties of biomaterials to mimic the cardiac extracellular matrix.Bioactive materials · 2022Review
- Identification ofInternational journal of molecular sciences · 2021Article
5 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Cardiac Na(+) channels encoded by the SCN5A gene are essential for initiating heart beats and maintaining a regular heart rhythm. Mutations in these channels have recently been associated with atrial fibrillation, ventricular arrhythmias, conduction disorders, and dilated cardiomyopathy (DCM).We investigated a young male patient with a mixed phenotype composed of documented conduction disorder, atrial flutter, and ventricular tachycardia associated with DCM. Further family screening revealed DCM in the patient's mother and sister and in three of the mother's sisters. Because of the complex clinical phenotypes, we screened SCN5A and identified a novel mutation, R219H, which is located on a highly conserved region on the fourth helix of the voltage sensor domain of Na(v)1.5. Three family members with DCM carried the R219H mutation.The wild-type (WT) and mutant Na(+) channels were expressed in a heterologous expression system, and intracellular pH (pHi) was measured using a pH-sensitive electrode. The biophysical characterization of the mutant channel revealed an unexpected selective proton leak with no effect on its biophysical properties. The H(+) leak through the mutated Na(v)1.5 channel was not related to the Na(+) permeation pathway but occurred through an alternative pore, most probably a proton wire on the voltage sensor domain.We propose that acidification of cardiac myocytes and/or downstream events may cause the DCM phenotype and other electrical problems in affected family members. The identification of this clinically significant H(+) leak may lead to the development of more targeted treatments.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.